Recurrent aphthous stomatitis (RAS), often referred to as "canker sores", is a common disease characterized by the repeated development of one to many painful ulcers of the oral mucosa. RAS is self-limited in nature but is associated with significant morbidity. The etiology of RAS is unknown and may be multifactorial. Current evidence most strongly supports a viral and/or autoimmune process. The purpose of this project is to examine the role of herpes simplex virus (HSV) is RAS and address whether the "autoimmune" injury is instead an HSV specific host response. Our hypothesis is that in patients with prior exposure to HSV (HSV antibody positive), the virus may exist in a quiescent state within multiple sites in the oral mucosa. Following different stimuli such as trauma or fever, there is expression of HSV specific antigens on the surface of mucosal cells. This stimulates an immune response resulting in the tissue damage seen as an ulcer. The HSV might reach the oral mucosa from sensory ganglia, many of which may be involved during the primary HSV infection, or by dissemination via peripheral blood leukocytes, and it may be present episodically or on a more continuous basis. This hypothesis is consistent with the observed similarities between herpes labialis and RAS in terms of prodromal symptoms and tendency to follow certain external stimuli and with previous evidence for involvement of cell mediated immune mechanism in the induction of the ulcers of RAS. We plan to investigate this hypothesis in the following ways: a) utilizing molecular biology techniques (polymerase chain reaction and in situ hybridization) to detect HSV nucleic acids (DNA and RNA, including latency associated transcripts) in lesions of RAS and in circulating leukocytes of RAS patients, b) defining the histopathology of RAS and the nature of the inflammatory reaction using immunocytochemistry, and c) examining the immunologic aspects of RAS by using an in vitro model which we have developed for the study of HSV-specific cytotoxic mechanisms. Long-term objectives include the following: a) a better understanding of RAS which may contribute to the development of therapy, and b) further knowledge of general application to the host immune response to HSV, including potential latency in the epithelium, mode of dissemination, and mechanisms of HSV specific cytotoxicity.